5-HT1F receptor agonism as a novel therapeutic strategy following spinal cord injury
5-HT1F 受体激动剂作为脊髓损伤后的新型治疗策略
基本信息
- 批准号:10516033
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-11-01 至 2023-10-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdvocateAgeAgonistAmericanAnimal ModelAreaBiogenesisBiologyBloodBlood VesselsCaregiversCaringClinicalClinical TrialsCompensationComplexConflict (Psychology)DataDevelopmentDevicesDiseaseDoctor of PhilosophyEventExhibitsFemaleFreedomFunctional disorderGoalsHealth Care CostsHealthcareHealthcare SystemsHomeostasisHumanHuman ResourcesIndividualInjuryInstitutionIntensive CareKnockout MiceLesionLocomotor RecoveryMediatingMediatorMedicalMigraineMilitary PersonnelMitochondriaMotor ActivityMusNatural regenerationNatureNeurosurgeonOxidantsOxidative StressOxygenPainParalysedPathologicPatient CarePatientsPersonsPharmaceutical PreparationsPharmacologyPhasePhase III Clinical TrialsQualifyingRecoveryRehabilitation therapySecondary toSerotoninSiteSpinal CordSpinal cord injuryTherapeuticTissuesTraumaUnited StatesUnited States Department of Veterans AffairsVeteranscare costsclinical applicationcombatdisabilitydrug discoveryexcitotoxicityexperienceimprovedinnovationlife time costloss of functionmalemitochondrial dysfunctionneuron apoptosisneuron lossnovelnovel therapeutic interventionoperationoxidative damagepatient populationpharmacologicprogramsreceptorrepairedresponserestorationserotonin receptorservice memberspinal cord repairtherapeutic target
项目摘要
The goal of this project is to study the 5-hydroxytryptamine 1F (5-HT1F) in stimulating mitochondrial
biogenesis (MB) and recovery from spinal cord injury (SCI). SCI is a devastating disorder often resulting in
loss of function below the injury site. While combat-related spinal trauma has been documented for centuries, in
recent years, service members have been threatened by more advanced warfare, such as rocket-propelled
grenades and improvised explosive devices, ultimately inducing more severe and complex injuries, including
SCI. Further, and importantly, advancements in personal protection, vehicular protection and medical capabilities
have allowed current military personnel to survive injuries that would have proven lethal in the past. The
devastating and debilitating nature of these injuries, however, including SCI, has not been lessened. The
Department of Veterans Affairs (VA) is the largest healthcare network for individuals suffering from SCI, providing
care for 25% of total victims in the United States. The development of pharmacological therapeutics for the
treatment of SCI would greatly benefit not only sufferers, but also the military healthcare system.
SCI is defined by direct trauma to the spinal cord, which disrupts the vasculature, leading to decreased oxygen
delivery within the area and reducing the ability of mitochondria to maintain cellular energetics. Neuronal loss of
mitochondrial function ultimately leads to excitotoxicity and oxidative stress, emphasizing the critical nature of
restoration of mitochondrial function following SCI. Evidence suggests that restoration of mitochondrial function
after injury could protect against further injury progression and enhance recovery. Studies investigating
mitochondria as a therapeutic target for SCI have only addressed individual aspects of mitochondrial function
and have proven largely inefficacious. Therapeutics pursuing reestablishment of mitochondrial homeostasis
through increased MB, however, following SCI could alleviate multiple facets of injury progression.
Our preliminary data indicate that the 5-HT1F agonism induces MB in the spinal cord of both naïve mice and
following SCI. Additionally, mice treated daily with the agonist LY344864 following SCI exhibited improved
mitochondrial homeostasis, as well as decreased lesion volume, and increased vascular and locomotor activity
by 7 days post-injury. Remarkably, LY344864 efficacy was similar when administration was initiated 1 or 8 h
post-SCI. This effect was not observed in mice lacking the 5-HT1F receptor, indicating that the presence of this
receptor is necessary for LY344864-induced MB. Lasmiditan is a potent and specific 5-HT1F receptor agonist
that is undergoing phase III clinical trials for migraine headaches. Treatment with lasmiditan beginning 1 h
post-SCI also induced MB and improved recovery. We hypothesize that treatment with
LY344864/lasmiditan following SCI will increase MB, resulting in improved locomotor recovery and
pain response, decreased neuronal death/dysfunction and increased vascular repair post-SCI. We
propose the following Specific Aims: 1) Determine MB, mitochondrial homeostasis (e.g. fission/fusion) and
function, locomotor capability and pain in response to LY344864/lasmiditan treatment post-SCI in female and
male mice; 2) Elucidate lesion volume, oxidative damage, and neuronal apoptosis in response to
LY344864/lasmiditan post-SCI in female and male mice and 3) Determine vascular recovery and blood-spinal
cord barrier (BSCB) integrity in response to LY344864/lasmiditan post-SCI in female and male mice
Successful completion of these studies could unveil 5-HT1F receptor-mediated MB as a potential strategy for
therapeutic treatment of SCI. Additionally, the proposed study will use a novel target, 5-HT1F receptor agonism,
and lasmiditan, which is undergoing clinical trials and has the potential to be repurposed for the treatment of
SCI. Finally, these studies will initiate drug administration 8 h after injury and be performed in both male and
female mice, strengthening clinical applicability.
本课题的目的是研究5-羟色胺1F(5-HT 1F)对线粒体膜电位的影响,
生物发生(MB)和脊髓损伤(SCI)的恢复。SCI是一种破坏性的疾病,
损伤部位以下的功能丧失。虽然战斗相关的脊柱创伤已经记录了几个世纪,
近年来,服役人员一直受到更先进战争的威胁,如火箭推进的
手榴弹和简易爆炸装置,最终造成更严重和复杂的伤害,
SCI.此外,重要的是,个人保护、车辆保护和医疗能力的进步
使现在的军事人员能够在过去被证明是致命的伤害中幸存下来。的
然而,包括SCI在内的这些损伤的破坏性和使人衰弱的性质并未减轻。的
退伍军人事务部(VA)是SCI患者最大的医疗保健网络,
占美国受害者总数的25%。药物治疗的发展
脊髓损伤的治疗不仅对患者,而且对军队医疗系统都有很大的好处。
SCI的定义是脊髓的直接创伤,破坏了血管系统,导致氧气减少
在该区域内递送并降低线粒体维持细胞能量的能力。神经元缺失
线粒体功能最终导致兴奋性毒性和氧化应激,强调了
脊髓损伤后线粒体功能的恢复。有证据表明线粒体功能的恢复
可以防止进一步的损伤进展并促进恢复。研究调查
线粒体作为SCI的治疗靶点仅涉及线粒体功能的个别方面
并且被证明是无效的。寻求重建线粒体稳态的治疗
然而,通过增加MB,SCI后可以缓解损伤进展的多个方面。
我们的初步数据表明,5-HT 1F激动剂在未处理小鼠和未处理小鼠的脊髓中诱导MB。
SCI之后。此外,SCI后每天用激动剂LY 344864治疗的小鼠表现出改善的
线粒体稳态,以及减少病变体积,增加血管和运动活性
受伤后7天。值得注意的是,LY 344864在给药后1小时或8小时开始时的疗效相似
SCI后。在缺乏5-HT 1F受体的小鼠中没有观察到这种效应,这表明这种受体的存在可能是一种免疫抑制剂。
受体是LY 344864诱导MB所必需的。Lasmiditan是一种有效的特异性5-HT 1F受体激动剂
正在进行偏头痛的第三阶段临床试验。lasmiditan治疗开始1小时
SCI后也诱导MB并改善恢复。我们假设,
SCI后LY 344864/lasmiditan将增加MB,从而改善运动恢复,
疼痛反应、神经元死亡/功能障碍减少以及SCI后血管修复增加。我们
提出了以下具体目标:1)确定MB,线粒体稳态(例如裂变/融合)和
SCI后女性对LY 344864/lasmiditan治疗的功能、运动能力和疼痛反应,
雄性小鼠; 2)阐明损伤体积、氧化损伤和神经元凋亡对
3)测定SCI后雌性和雄性小鼠中的血管恢复和血脊髓损伤。
SCI后雌性和雄性小鼠对LY 344864/lasmiditan的脊髓屏障(BSCB)完整性反应
这些研究的成功完成可能揭示5-HT 1F受体介导的MB作为一种潜在的策略,
SCI的治疗。此外,拟议的研究将使用一种新的靶点,5-HT 1F受体激动剂,
和lasmiditan,这是正在进行临床试验,并有可能被重新用于治疗
SCI.最后,这些研究将在损伤后8小时开始给药,并在男性和女性中进行。
雌性小鼠,增强临床适用性。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Rick G Schnellmann其他文献
Rick G Schnellmann的其他文献
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{{ truncateString('Rick G Schnellmann', 18)}}的其他基金
Enhanced Mitochondrial Function to Increase Effectiveness of Post-Stroke Rehabilitation
增强线粒体功能以提高中风后康复的有效性
- 批准号:
10490270 - 财政年份:2019
- 资助金额:
-- - 项目类别:
5-HT1F receptor agonism as a novel therapeutic strategy following spinal cord injury
5-HT1F 受体激动剂作为脊髓损伤后的新型治疗策略
- 批准号:
9890471 - 财政年份:2019
- 资助金额:
-- - 项目类别:
5-HT1F receptor agonism as a novel therapeutic strategy following spinal cord injury
5-HT1F 受体激动剂作为脊髓损伤后的新型治疗策略
- 批准号:
10300436 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Enhanced Mitochondrial Function to Increase Effectiveness of Post-Stroke Rehabilitation
增强线粒体功能以提高中风后康复的有效性
- 批准号:
10268186 - 财政年份:2019
- 资助金额:
-- - 项目类别:
5-HT1F receptor agonism as a novel therapeutic strategy following spinal cord injury
5-HT1F 受体激动剂作为脊髓损伤后的新型治疗策略
- 批准号:
10058204 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Urinary Biomarkers of Renal Mitochondrial Dysfunction
肾线粒体功能障碍的尿液生物标志物
- 批准号:
9055870 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Urinary Biomarkers of Renal Mitochondrial Dysfunction
肾线粒体功能障碍的尿液生物标志物
- 批准号:
8522644 - 财政年份:2013
- 资助金额:
-- - 项目类别:
5-HT Stimulation of Mitochondrial Biogenesis and Acute Kidney Injury
5-HT 刺激线粒体生物发生和急性肾损伤
- 批准号:
8198361 - 财政年份:2010
- 资助金额:
-- - 项目类别:
5-HT Stimulation of Mitochondrial Biogenesis and Acute Kidney Injury
5-HT 刺激线粒体生物发生和急性肾损伤
- 批准号:
8597388 - 财政年份:2010
- 资助金额:
-- - 项目类别:
5-HT Stimulation of Mitochondrial Biogenesis and Acute Kidney Injury
5-HT 刺激线粒体生物发生和急性肾损伤
- 批准号:
8391608 - 财政年份:2010
- 资助金额:
-- - 项目类别:
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